Prevention of breast cancer using medical therapy (chemoprevention) is now possible. Clinical trials have demonstrated that treatment of normal women at high risk of breast cancer with anti-estrogen drugs (selective estrogen receptor modulators, or SERMs) can substantially reduce their risk of developing breast cancer. However, SERMs are frequently not used by high risk women because they are not 100% effective and because chronic therapy with anti-estrogens has significant side effects. In addition, while long-term anti-estrogens reduce the risk of ER-positive breast cancer, they do not reduce ER-negative breast cancer. Thus, more effective and less toxic strategies to prevent all types of breast cancer are needed. We have previously shown that RXR-selective retinoids (rexinoids) prevent the development of ER-negative breast cancer in preclinical models in mice, and that the combination of SERMs and rexinoids is particularly effective. We have also conducted clinical trials using SERMs or rexinoids (as single agents) in high risk women and have demonstrated that these agents are tolerable. Here we will test the hypotheses that both ER-positive and ER-negative breast cancer can be prevented by combining drugs with different mechanisms of action, that by combining these drugs we will induce apoptosis in premalignant mammary tissue, and that short-term use of combined preventive agents will result in effective prevention with reduced side effects. (1) We will investigate whether chronic therapy with the SERM tamoxifen and the rexinoid bexarotene will totally prevent breast cancer in the p53-null mouse model (in which both ER-positive and ER-negative breast cancers develop) and determine whether this combination therapy induces apoptosis in precancerous breast cells. (2) We will investigate whether short-term treatment with tamoxifen and bexarotene will effectively prevent the development of breast cancer, and we will investigate the mechanism by which this short-term treatment can provide long-lasting protection. (3) We will conduct a Phase II clinical trial in premenopausal women at increased risk of breast cancer using the combination of tamoxifen plus bexarotene to determine whether short-term treatment in high risk women will induce apoptosis or suppress proliferation of mammary epithelial cells. These studies will lay the foundation for testing this combination of an anti-estrogen and a rexinoid in women at risk of breast cancer in future Phase III breast cancer prevention trials.